This NephJC will be a joint effort between the nephrology community and the socially active rheumatologists. We enlisted one of the top rheumatologists on Twitter, Dr. Paul Sufka to write the introduction for this week's #NephJC. So offer a warm welcome to the rheumatologists and enjoy Paul's introduction.

Background on establishment of the use of rituximab for ANCA-associated vasculitis

Until recently, the only standard therapy for treatment of ANCA-associated vasculitis had been induction with cyclophosphamide plus glucocorticoids. In 2010, the RAVE and RITUXVAS trials respectively established rituximab as non-inferior therapy for the induction of systemic and renal ANCA-associated vasculitis, with similar adverse events.

The RAVE trial compared rituximab to oral cyclophosphamide, with a primary outcome of complete remission and tapering of glucocorticoids at 6 months.

Rituximab group: 63/99 patients (64%)

Cyclophosphamide group: 52/98 patients (53%)

Despite a trend toward improved outcomes in the rituximab group, the RAVE study was powered as a non-inferiority trial, and the differences between the groups were not statistically significant (p=0.09, 95% CI -3.2 to 24.3).

Again, despite the numerical trend, this data was only able to support rituximab as non-inferior to cyclophosphamide. Additional analysis showed that in patients with relapsing disease, rituximab was superior at 6 months (p=0.01) and 12 months (p=0.009), but this effect did not extend out to 18 months (p=0.06).

What is the role of rituximab in maintenance therapy for ANCA-associated vasculitis?

Until now, only retrospectivedata has suggested that rituximab might be useful as a maintenance strategy for ANCA-associated vasculitis. This question was addressed in our current journal club article:

Study design

Patients

This study recruited patients aged 18-75 with newly diagnosed ANCA-associated vasculitis who were in complete remission after treatment with glucocorticoids plus pulsed cyclophosphamide. Disease activity was measured using BVAS, a standard vasculitis activity measure. Patients who previously received rituximab were excluded.

Treatment protocol

Induction of remission in both groups was achieved with the following protocol:

In both groups, prednisone was further tapered to approximately 5 mg/day for at least 18 months, after which prednisone could be further tapered at investigator discretion.

End points

The primary end point was the percentage of patients with major relapse (reappearance or worsening of disease with a BVAS >0 and involvement of at least one major organ, a life-threatening manifestation, or both) at month 28.

Secondary end points:

Rates of minor relapse

Adverse events

Mortality

Statistics

Under the hypothesis that rituximab would decrease major relapses by 25% at month 28, assuming 5% exclusion or dropout, to have 80% statistical powerand a 2-sided alpha risk of 0.05, 118 patients had to be enrolled in the trial.

Results

115 patients were enrolled (87 with GPA, 23 with MPA, and 5 with renal-limited ANCA-associated vasculitis). 58 received azathioprine and 57 received rituximab. Patient demographics were not significantly different in either group. 80% of patients had newly diagnosed disease, and 20% had relapsing disease.

To put it another way, in the authors words, “hence, to avoid one major relapse, 4 patients (95% CI, 3 to 9) had to be treated with systematic rituximab infusions rather than with azathioprine.“

Secondary end points

Minor relapses were not statistically different between each group, with 9/58 (16%) in the azathioprine group and 6/57 in the rituximab group (11%) (p=0.43).

Rates of infection were similar in both groups, with 8/58 (14%) in the azathioprine group and 11/57 (19%) in the rituximab group.

There were two deaths in the azathioprine group, one with vasculitis involvement of the aortic valve who had a major relapse and received pulse steroids but died of E. coli bacteremia. The second patient had developed pancreatic cancer.

Author’s discussion

The authors concluded that

...in the present study, rituximab was superior to azathioprine at maintaining remission of ANCA-associated vasculitis; this was especially true for granulomatosis with polyangiitis, which was the condition seen in most of the study population.

Our data also show that successive 500-mg infusions of rituximab, given every 6 months up to month 18 after remission, were not associated with more frequent severe adverse events than azathioprine.

Interestingly, the authors note that the 6-month interval between rituximab infusions was chosen based on expected B-cell reconstitution and relapses after a median of 1 year.

They also state that a single 500 mg rituximab dose was chosen because patients were already in remission (i.e. B-cell deplete) and in hopes of decreasing risk of infection.

Study limitations:

Unblinded.

Unable to generalize to all patient types with ANCA-associated vasculitis since most had PR3-ANCA/GPA.

Leaving prednisone tapering up to discretion of investigators after 18-months (although authors note that only 2/20 relapsed patients had stopped prednisone).

Azathioprine maintenance until month 22, with a gradual taper (although 8 relapses occurred in the first 12 months at a dose of 2 mg/kg, and only 2 relapses occurred between months 12 and 22).

Another important point from the authors is that “several major relapses (7 of 17 in the azathioprine group and 2 of 3 in the rituximab group) occurred after treatment with the trial maintenance drugs was stopped.”

My thoughts

Having personally used rituximab in the clinical setting for both remission-induction and treatment of relapse for ANCA-associated vasculitis, and knowing that B-cells play a significant role in disease activity, I was not surprised that rituximab would be an effective therapy. This being said, I certainly did not expect a NNT of only 4 patients. I was also impressed were able to achieve these results using only single 500 mg doses of rituximab every 6 months, which may be important not only for potential decreased infectious risks, but may have financial implications as well.

One concerning observation in this study is that after stopping maintenance therapy in either group led to several major relapses. I have often wondered if we can ever safely stop all immunosuppressive therapy in these patients, and if so, how to identify which patients this can be safely achieved.